International Circulation: One of your talks during CIT 2011 will involve the 2nd generation of drug eluting stents (DES). Please summarize the main advantages of these 2nd generation stents over the previous generation?
Prof David Kandzari: I prefer not to differentiate between the drug eluting stents as to regards to whether they are first， second or more advanced generations. I Think what we have learnt is a broader theme from comparative DES trials is that not all stents are created equally whether they are polymers， comprised of metal or contain drugs which are anti-proliferative. For the current newer second generation drug eluting stents we have learnt some important lessons from the previous generation. The first is that I would to emphasize that not all stents are created equally. Through long term follow from previous comparative and more recent comparative trials evaluating first and second DES we have learnt there are important differences in these stents with regards to not only angiographic efficacy such as late lumen loss but more importantly patient based clinical outcomes such as the need for repeat revascularization， death， myocardial infarction and stent thrombosis. Secondly， not all stents will behave as they do in clinical trials as they do in clinical practice. In other words not all clinical trials are representative of how a stent will fare in real world practice. We have learnt this from the 2006 FDA panel meeting for example that off label use may be associated with worse outcomes. This more importantly enforces the idea that we should follow the outcomes of these patients treated in broad unselected patient populations. This is because more recent studies suggest that DES might be associated with lower mortality with improved outcomes. Thirdly， is that given the outcomes of DES today and the lowest rates of repeat revascularization we have ever observed with everolimus eluting stents and sirolimus -eluting stents as well as the lowest rates of stent thrombosis and cardiovascular death， the challenge of raising this bar will be quite difficult. Future stents such as ones with a bioresorbable polymer or a bioresorbable stent altogether will find it very difficult to demonstrate any superiority.
International Circulation: In other words do you think some of these trials aimed to demonstrate inferiority rather than superiority?
Prof David Kandzari: Indeed， there is always a succession of non-inferiority trials which can lead to new approvals. There is a concept called statistical creep whereby a succession of non inferiority trials could result in the product becoming no better than what it was and so we have to be very cautious this respect. It is easier to put a new stent on the market based on non inferiority. This is because to demonstrate superiority in terms of stent thrombosis and safety from these bioresorbable stents given that we are already seeing fairly low rates of thrombosis from these second generation drug eluting stents would be very difficult .
International Circulation: Therefore in order to demonstrate any noticeable difference we will need to design a very large trial and enrol many patients?
Prof David Kandzari: Yes， by a magnitude of tens of thousands of patients and because of this issue and because of the changes of the regulatory requirements all over the world where they are being more stringent and restrictive in terms of margins of non-inferiority， it is going to take a very large trial to get a new stent onto the market.
International Circulation: For these large trials do you think this will make China a more attractive option to conduct these trials?
Prof David Kandzari: I think there are many important points which China a very attractive option to conduct early phase and advanced stent trials. One of the reasons is that China represents a significant proportion of the population in the world and cardiovascular death is emerging as one of the leading cause of death. This alone makes evaluating new therapies and drugs attractive. Secondly， on behalf of the Chinese clinicians and investigators who are now organizing in a way that is creating a very solid infrastructure for clinical trial conduct， design and follow up. We are seeing an increasing volume of publications from China demonstrating both the systematic approach to trial design and execution as well as the credibility of the data. In the U.S for example the FDA has recognized that in order to conduct a large trial it will need to be global. We cannot conduct a trial with thirty- forty- thousand patients in the United States alone. Therefore a more global representation is needed and certainly China represents one of the leading geographies.
International Circulation: For these second generation stents what problems do you still see?
Prof David Kandzari: I think these fall into twofold. Number one we are still seeing progression of repeat revascularization after around a year or 9 months after the trial endpoint and so we know that events continue to occur in some patients. This is due to failure of efficacy， late stent stenosis with selected drug eluting stents and very late stage thrombosis. Part of the late thrombosis issue is that we are now very careful in following these patients. When bare metal stents were first approved they were approved on thirty day data with no plans for long term follow up so we never knew if it was a anecdotal clinical observation whether these events can occur late as well. And now that we are following patients more carefully we do recognize that events do persist. Another is the perceived lifetime commitment for some doctors for dual anti platelet therapy in patients with these stents. If we can test these new stents and new strategies such as shorter durations of anti-platelet therapy or in complex diseases such as left main disease I think this is the direction where new DES trials should be moving rather than trying to get a new product in the market.
International Circulation: Is it not difficult to keep patients on lifelong anti-platelet therapy?
Prof David Kandzari: I am a big proponent for shorter durations of anti-platelet therapy or at least evaluate them not because think patients should be taken off therapy after 6 months but because we recognize that adherence or compliance over long term follow up despite our best intentions just does not occur in real life practice. Even in contemporary trials by 5 years maybe 25%-30% of the patients are still taking aspirin and clopidogrel therapy. I will like to remind clinicians that we just do not have evidence that staying on long term anti-platelet therapy actually is going to reduce the risk of stent thrombosis.
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